On a global basis, urinary tract infections (UTIs), which are among the most common infectious diseases in the United States, occur -150 million times annually and account for more than $6 billion in direct health care costs. UTIs primarily affect women because of the female- anatomy and the ascending nature of the disease. The Gram-negative bacterium Escherichia coli is the most common cause of these infections which account for significant morbidity. In addition, to the original infection one of the major clinical problems is recurrence. A woman treated for an uncomplicated UTI has a 25-50% chance of developing a recurrent infection. It has generally been assumed that UTIs are caused by non-invasive bacteria, that they are acute in nature, and are self-limited. It has also been assumed that recurrent infections are due to re-inoculation of the urinary tract with E.coli from an intestinal or vaginal reservoir. Recent evidence suggests that this dogma may in some cases be incorrect and misleading and could be interfering with the proper evaluation and treatment of these infections. This proposal seeks to elucidate the molecular and epidemiologic basis of acute and recurrent UTIs. Special emphasis will be placed on better defining the epidemiology of UTIs, determining the presence of persistent bacterial bladder and vaginal reservoirs following acute symptomatic UTI in women and elucidating the molecular factors involved in the host-pathogen interaction. The temporal, associations between asymptornatic and symptomatic bladder infection and vaginal colonization in the clinical setting will be assessed. Molecular characterization of the virulence determinants in well-characterized uropathogenic strains will be elucidated by blending a powerful genetic system with functional genomics, defined in vitro and murine models, biochemistry, cell biology, and high resolution electron microscopy. The mechanistic details of how the bladder responds to infection, and how specific virulence. factors affect this host response will be determined using microarray, quantitative RT-PCR and laser capture microdis section. This proposal represents an intricate and integrated network between three projects and will lead to a new understanding of the host-pathogen interactions that occur throughout the infectious cycle including the host defense response in the bladder and the virulence mechanisms by which bacterial pathogens subvert these defenses. Results of this research could revolutionize the way UTIs are evaluated and lead to new and better ways to treat and prevent this infection that primarily affects women.